Background: Women present more commonly with atypical angina, false-positive exercise test, and normal/nonobstructive coronary angiogram. It thus becomes essential to identify the predictors of obstructive coronary artery disease (CAD) in women to avoid unnecessary invasive angiograms. Methods: We prospectively recorded the data of consecutive 578 women who underwent coronary angiography in our institute for typical/atypical chest pain suspected to be secondary to CAD. Results: Normal coronaries/nonobstructive CAD were seen in 273 (47.2%) patients, whereas 305 (52.8%) patients were found to have obstructive CAD (P < 0.0001). On multivariate logistic regression analysis, the presence of typical angina, age >55 years, smoking, diabetes mellitus, hypertension, low-density lipoprotein cholesterol >150 mg/dl, and high-density lipoprotein cholesterol <40 mg/dl were found to be independent predictors of obstructive CAD. Conclusion: These risk predictors can help in the reliable assessment of pretest likelihood of obstructive CAD in women, thereby avoiding many unnecessary invasive coronary angiograms. Further larger studies are warranted to validate these results and propose accurate prediction models for the diagnosis of obstructive CAD in women.

Coronary artery disease (CAD) is the leading cause of mortality in both men and women worldwide.[1] However, CAD in women presents a unique and complex challenge to clinicians as a result of larger symptom burden and more atypical presentation.[2] Women reportedly have lower rates of obstructive CAD despite more symptoms and higher rates of myocardial ischemia and mortality compared to similarly aged men.[3] Coronary microvascular dysfunction is a frequent cause of chest pain among women, in the absence of obstructive CAD.[4] There is overwhelming evidence that women with suspected ischemia are frequently underinvestigated.[5] Treadmill test (TMT) has a very limited accuracy in women, especially because of the resting ST-T wave changes, lower electrocardiogram voltage, and certain hormonal factors. Its sensitivity and specificity for the diagnosis of obstructive CAD in women range from 31% to 71% and from 66% to 86%, respectively.[6] Another important limitation of TMT in women is their inability to exercise for a longer duration to their maximum aerobic potentials.[6]

Similar to TMT, other common observations such as electrocardiographic changes, myocardial perfusion defects, and regional wall motion abnormalities have limited value in women undergoing evaluation for CAD.[7] Although coronary angiography is the gold standard to diagnose obstructive disease and is generally a safe procedure, death and procedural myocardial infarction occur as complications in 0.1% patients.[8] Vascular site complications are more frequently observed in as high as 8% patients depending on the operator's expertise and occur more frequently in women.[7],[8] The greater prevalence of atypical symptoms, limited utility of noninvasive diagnostic testing, and frequent finding of normal/nonobstructive CAD on angiography make it imperative to identify the determinants of obstructive CAD in women before they undergo invasive testing.

Unfortunately, no prior study has identified the determinants of obstructive CAD in Indian women presenting with ischemic symptoms. The present study was designed to bridge this knowledge gap.

Methods

We prospectively enrolled all the female patients under evaluation for chest pain with a clinical suspicion of CAD in our institute over a 2-year period (March 1, 2015–February 28, 2017). Patients who refused to provide detailed informed consent and those having acute coronary syndrome, prior myocardial infarction, electrocardiographic or echocardiographic evidence of old myocardial infarction, prior percutaneous coronary intervention, or coronary bypass grafting were excluded from the study. Other exclusion criteria included the presence of chronic kidney disease, moderate-to-severe pulmonary artery hypertension, moderate-to-severe valvular heart disease, congenital heart disease, heart failure, cardiomyopathy, and any traumatic or infective cause of chest pain or any serious medical/psychiatric illness that would compromise patient's safety. TMT was not mandatory. However, among patients in whom TMT had been done, if they had atypical chest pain with a negative TMT result, they were also excluded. The study protocol was approved by the ethical committee of our institute. Clinical and angiographic data were recorded systematically. Based on angiographic results, patients were divided into two groups: those with normal epicardial coronary arteries or nonobstructive CAD (Group 1) and those with obstructive CAD (Group 2). Obstructive CAD was defined as the presence of at least one major epicardial coronary artery or its branch with >50% lumen diameter narrowing. The type of angina was classified as typical or atypical. Typical angina was labeled if all of the following criteria were met: (1) substernal chest pain, (2) provoked by exertion or emotional stress, and (3) relieved by rest and/or nitrates within minutes. If 1–2 of the criteria were present, the symptoms were classified as atypical angina. Hypertension was defined as patient on treatment for elevated blood pressure or a systolic pressure ≥140 mmHg and/or diastolic pressure ≥90 mmHg. Diabetes was defined as fasting blood glucose equal to or >126 mg/dl or 2-h postprandial blood glucose >200 mg/dl or HbA1c ≥6.5% and/or patients with a history of diabetes mellitus or who are receiving antidiabetic therapy. Smoker was defined as the one who regularly smoked an average of one or more cigarettes a day for at least 1 year. Patients who had given up smoking for >12 months were considered ex-smokers. Family history of premature CAD was considered positive in the presence of CAD in a first-degree male relative 55 years or less in age and/or a first-degree female relative 65 years or less in age. Patients on lipid-lowering therapy or lipid levels in the following range were considered to have dyslipidemia: total cholesterol >240 mg/dl, triglycerides >150 mg/dl, low-density lipoprotein (LDL) cholesterol ≥130 mg/dl, and high-density lipoprotein (HDL) cholesterol ≤40 mg/dl. Overweight/obesity was labeled in those with a body mass index (BMI) ≥23 kg/m2. Continuous variables were reported as the mean ± standard deviation, and categorical variables were presented as proportions. Chi-square test and student t-test were used to compare differences between the groups. All tests of significance were two-tailed, and statistical significance was defined as P < 0.05. All statistical analyses and the multivariable logistic regression analysis were performed using Epi Info version 3.4.3 (Centre for disease control and prevention, Atlanta, Georgia, United State).

Results

Study population

We prospectively analyzed the data of consecutive 578 women who underwent coronary angiography in our institute for typical/atypical chest pain suspected to be secondary to CAD. On data analysis, 273 (47.2%) patients were having normal coronaries/nonobstructive CAD and 305 (52.8%) patients were found to have obstructive CAD (P < 0.0001). The comparison of baseline characteristics and risk factors between the study groups has been provided in [Table 1].

Table 1: Clinical characteristics according to the presence and absence of obstructive disease

Among the patients presenting with atypical angina, majority (86.6%) of the patients were found to have normal/nonobstructive coronary arteries, whereas only 13.4% had obstructive CAD. In contrast, obstructive CAD was more commonly seen with those presenting with typical chronic stable angina (66.2% vs. 33.8%, P < 0.01) [Figure 1].

Figure 1: The presence of obstructive versus normal/nonobstructive disease in the study population according to the diagnosis at presentation.

The relationship of a cluster of the identified risk determinants with a number of diseased vessels was also analyzed [Table 3]. The significant risk determinants such as age >55 years, hypertension, diabetes, dyslipidemia, smoking, and typical angina, which were having significant causal relationship with CAD on multivariate analysis, were the only ones considered. Among patients with none of these risk determinants, all were found to have normal coronary arteries or nonobstructive CAD. It was observed that as the number of risk determinants increased, the finding of normal coronaries/nonobstructive CAD became less frequent, while that of obstructive CAD became more common. The finding of double-vessel disease and triple-vessel disease increased significantly, especially when the cumulative risk determinants were four or more in number [Table 3].

Table 3: Relationship of number of risk determinants to the angiographic severity of coronary artery disease

Using multivariate logistic regression analysis, we identified certain risk factors/parameters which were found to be independent determinants of the presence of obstructive CAD among women [Table 2]. There is hardly any data available from the contemporary Indian studies regarding the predictors of obstructive CAD in women.[9],[10] It is an already proven fact that the increased prevalence of established risk factors is responsible for the epidemic of CAD in India.[11] The present study also demonstrated that the presence and extent of CAD increased as the number of above-mentioned risk determinants increased in women [Table 3]. The present study revealed that the exercise treadmill testing has a limited role in predicting the presence of obstructive CAD in Indian women presenting with chest pain. Exercise stress test was performed in less than half (43.3%) of the study population. Similar pattern of its underuse has been documented in a recent Indian study.[9] The main reasons for underuse included patients' inability to walk on treadmill. However, the role of physician's inertia in advising an exercise stress test before coronary angiogram should not be underestimated. This is alarming since despite a very limited accuracy in women, a negative exercise stress test provides a significant diagnostic and prognostic value.[6]

The study identified the presence of typical angina (odds ratio [OR] (95% confidence interval [CI]) = 17.67 [8.88–35.14]) and smoking (OR [95% CI] = 15.28 [6.27–37.21]), as the two most significant predictors of obstructive CAD. This highlights the role of a detailed and focused history while inquiring the nature of angina in women. Smoking may be more detrimental in women than in men. Female smokers die 14.5 years earlier than female nonsmokers. Data from the INTERHEART study showed that women smokers have double the risk of developing myocardial infarction than those who do not smoke.[12] It is well known that the prevalence of CAD increases with age in both men and women. This is in part because of increase in the prevalence of cardiovascular risk factors with age.[13] The causative role of diabetes, hypertension, and high LDL-cholesterol in the genesis of CAD is well known.[12],[13],[14] Our study also revealed a causative role of low HDL cholesterol in obstructive CAD. Although prior data are conflicting regarding the role of low HDL cholesterol, some evidence exist which suggest a causative role, especially in women.[15] Premature CAD in first-degree female relatives is a relatively more potent family history risk factor than is premature CAD in male relatives.[12] Surprisingly, it did not increase the risk of obstructive CAD in the present study. Overweight/obesity is associated with other risk factors such as diabetes and hypertension, thereby leads to increased risk of CAD. Interestingly, overweight/obesity (BMI >23 kg/m2) was not associated with the risk of obstructive CAD in our study (OR [95% CI] = 0.71 [0.33–1.48]). This may be due to the fact that obesity was defined by BMI alone in the present study and that too as per the latest Asian recommendations.[16] Prior studies have shown that the pattern of obesity is related to cardiovascular disease (CVD); while waist circumference (>35 inches), indicative of visceral obesity, is related to the elevated risk for CVD, elevated BMI alone is not.[17] Unfortunately, waist circumference was not recorded in the present study.

The past studies have shown that there is a high prevalence of atypical chest pain, especially in young women. Furthermore, they often have lower rates of obstructive CAD compared to similarly aged men. In our study also, one-fourth of the women had atypical chest pain, and majority of them had normal/nonobstructive CAD [Figure 1]. Identification of the above-mentioned risk determinants would thus help in the avoidance of many unnecessary invasive coronary angiograms, especially in women with atypical symptoms and without any of the predictive risk determinants.

The limitations of the study included its observational, single-center design and lack of follow-up data. Other important limitations include a lack of estimation of fractional flow reserve in lesions between 50% and 70% stenosis and a lack of inclusion of novel risk factors such as serum homocysteine, lipoprotein (a), and high-sensitivity C-reactive protein. The issue of CAD in women is not necessarily one of the obstructive diseases alone but of the burden of atherosclerosis. Finally, we did not address several women-specific risk factors for CAD including gestational diabetes and hypertension, age at menopause, use of hormones, and breast cancer therapies.

Conclusion

The prospective study of 578 patients identified certain risk determinants of obstructive CAD in female patients. Female patients present commonly with atypical angina, and TMT is often not done or inconclusive. Furthermore, high percentages have nonobstructive CAD or normal coronary arteries despite having typical angina. The risk predictors can help in the reliable assessment of pretest likelihood of CAD, thereby avoiding many unnecessary invasive coronary angiograms. Further larger studies are warranted to validate these results and propose accurate prediction models for the diagnosis of obstructive CAD in women.